A systematic review and meta-analysis of the effectiveness of primary thromboprophylaxis in acute lymphoblastic leukemia during early-phase therapy including asparaginase or its prolonged form.

Asparaginase is essential in the initial management of acute lymphoblastic leukemia (ALL) but frequently leads to venous thromboembolism (VTE). Using anticoagulants for primary VTE prevention has been studied with no consensus. We conducted a systematic literature search in PubMed, Scopus, and Web of science and performed random-effect meta-analysis using Mantel-Haenszel method in RevMan 5.4 to analyze primary pharmacological thromboprophylaxis during asparaginase treatment in early-phase (induction, consolidation, or intensification phase) therapy in patients with ALL with all ages and followed with subgroup analysis by age. Meta-analysis of 13 articles describing the effect of antithrombin supplementation in 1375 patients showed that antithrombin prophylaxis decreases the risk of VTE by 43% (RR, 0.57; 95% CI, 0.38 - 0.83; p=0.004), with mild heterogeneity (I2=35%, p=0.10) and moderate certainty by GRADE. 8 articles included for meta-analysis of low-molecular weight heparin (LMWH) treatment in 612 patients showed that it decreased the risk of VTE by nearly 40% (RR, 0.61; 95% CI, 0.45 - 0.81; p=0.00081), with minimal heterogeneity (I2=14%, p=0.31) but low certainty. Subgroup analysis showed that only prophylaxis with antithrombin supplementation significantly decreased the VTE rate in adult patients with moderate certainty. In pediatric patients, one nonrandomized prospective study showed that LMWH combined with antithrombin has a better thromboprophylaxis effect than antithrombin alone. In the PREVAPIX-ALL trial, prophylaxis with direct factor Xa inhibitor Apixaban did not benefit children younger than 18 years except for cases of obesity. We concluded that thromboprophylaxis with antithrombin is effective in ALL patients older than 18 years during the early phase of therapy, and LMWH combined with antithrombin supplementation might be effective for pediatric patients with ALL. Apixaban is effective in pediatric ALL patients with obesity and needs further study in other high-risk patients.

Treatment of acute pulmonary embolism after catheter-directed thrombolysis with dabigatran vs warfarin: Results of a multicenter randomized RE-SPIRE trial.

BACKGROUND: Thrombolytic therapy is effective method in the high-risk acute pulmonary embolism (PE) treatment. Reduced-dose thrombolysis (RDT) plus oral anticoagulation therapy is effective and safe method in the moderate and severe PE treatment. It is leading to good early and intermediate-term outcomes. In the RE-COVER and RE-COVER II studies, dabigatran showed similar effectiveness as warfarin in the treatment of acute PE. Dabigatran leads to fewer hemorrhagic complications and is not inferior in efficacy to warfarin in the prevention of PE after mechanical fragmentation and RDT (catheter-directed treatment [CDT]+RDT) in patients with high and intermediate to high PE risk. We sought to evaluate the efficacy and safety (incidence of clinically significant recurrence of venous thromboembolic complications and deaths) during a 6-month course of treatment with dabigatran or warfarin in patients with high and intermediate to high acute PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT). METHODS: The RE-SPIRE is a prospective, multicenter randomized double-arm study. Over a 5-year period, 66 consecutive patients with symptomatic high and intermediate to high PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT) were randomized into two groups within the next 48 hours. The first group continued treatment with dabigatran 150 mg twice a day for 6 months; the second group continued treatment with warfarin under the control of international normalized ratio (2.0-3.0) for 6 months. Both groups received low molecular weight heparins for 2 days after surgery. Then, group 1 continued to receive low molecular-weight-heparin for 5 to 7 days, followed by a switch to dabigatran at a dosage of 150 mg two times a day. Group 2 received both low-molecular-weight heparin and warfarin up to an international normalized ratio of >2.0, followed by heparin withdrawal. The follow-up period was 6 months. RESULTS: There were 63 patients who completed the study (32 in the dabigatran group and 31 in the warfarin group). In both groups, there was a statistically significant decrease in the mean pulmonary artery pressure. The mean pulmonary artery pressure at the 6-month follow-up after surgery was 24 mm Hg (interquartile range, 20.3-29.25 mm Hg) in the dabigatran group and 23 mm Hg (interquartile range, 20.0-26.3 mm Hg) in the warfarin group. The groups did not differ statistically in the deep vein thrombosis dynamics. Partial recanalization occurred in 52.0% vs 73.1% in the dabigatran and warfarin groups, respectively (P = .15). Complete recanalization occurred in 28.0% vs 19.2% in the dabigatran and warfarin groups, respectively (P = .56). The groups did not differ in the frequency of major bleeding events according to the International Society for Thrombosis and Hemostasis (0% vs 3.2% in the dabigatran and warfarin groups, respectively; P = 1.00). However, there were more nonmajor bleeding events in the warfarin group than in the dabigatran group (16.1% vs 0%, respectively; P = .02). CONCLUSIONS: The results of the study show that dabigatran is comparable in effectiveness to warfarin. Dabigatran has greater safety in comparison with warfarin in the occurrence of all cases of bleeding in the postoperative and long-term periods. Thus, dabigatran may be recommended for the treatment and prevention of PE after CDT with RDT in patients with high and intermediate to high PE risk.

The Rise and Fall of Antithrombin Supplementation in Cardiac Surgery.

Various cohort studies, both retrospective and prospective, showed that low antithrombin levels after cardiac surgery (at the arrival in the intensive care unit and during the next days) were associated with a number of adverse outcomes, including surgical reexploration and thromboembolic events, eventually leading to prolonged stay in the intensive care. Values lower than 58% to 64% of antithrombin activity were indicative of this higher morbidity with good sensitivity and specificity. The scenario generated the hypothesis that low antithrombin levels needed to be corrected by supplementation to improve postoperative outcome. However, randomized controlled studies run to test this idea failed to demonstrate any benefit of antithrombin supplementation, showing no effects on outcome, neither as preemptive preoperative strategy nor for treating postoperative low antithrombin values. In addition, randomized trials highlighted that those patients who received antithrombin experienced significantly higher incidence of acute kidney injury with a pooled odds ratio of 4.41 (95% CI, 1.90-10.23; P = .001). A strongly decreased thrombin activity after antithrombin correction may eventually affect the efficiency of the glomerular filtration and cause the deterioration of kidney function, but underlying biological mechanisms remain unclear. In conclusion, low levels of antithrombin activity after cardiac surgery should be considered as a marker of greater severity of the patient's conditions and/or of the complexity of the surgical procedure. There are no indications for antithrombin supplementation in cardiac surgery unless for correcting heparin resistance.

Management of DOAC in Patients Undergoing Planned Surgery or Invasive Procedure: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary "anticoagulation team" with the aim to define the optimal perioperative management of anticoagulation.

Impact of different renal function equations on direct oral anticoagulant concentrations.

The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft-Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.

A strategy of idarucizumab for pericardial tamponade during perioperative period of atrial fibrillation ablation.

OBJECTIVE: To investigate theoptimal idarucizumab (dabigatran antagonist) usage strategy for patients with acute pericardial tamponade receiving uninterrupted dabigatran during catheter ablation for atrial fibrillation (AF). METHODS: Ten patients presenting acute pericardial tamponade while receiving uninterrupted dabigatran during catheter ablation for AF in Beijing Anzhen Hospital from January 2019 to July 2020 were enrolled and retrospectively analyzed. A "wait and see" strategy of idarucizumab was carried out for all patients; in brief, idarucizumab was applied following pericardiocentesis, comprehensive evaluation of bleeding and hemostasis. RESULTS: There were five males, five paroxysmal AF, and the average age of the patients was 64.0 ± 9.8 years. Among the 10 patients, four were treated with dabigatran 110 mg, six were treated with dabigatran 150 mg, and one was simultaneously given clopidogrel. The average time from pericardial tamponade to the last dose of dabigatran was 8.2 ± 3.4 h. All patients underwent pericardiocentesis successfully, and the average drainage volume was 322.5 ml (220.0 ± 935.0 ml). For reversal anticoagulation, six patients received protamine, and five patients received idarucizumab. Of the five patients who were treated with idarucizumab, four presented exact hemostasis, except for one patient who underwent continuous drainage and finally received surgery repair. The average time to restart anticoagulation was 1.1 ± 0.3 days after the procedure, and no rebleeding, embolism or deaths were observed. CONCLUSION: The "wait and see" strategy of idarucizumab for acute pericardial tamponade during the perioperative period of catheter ablation for AF may be safe and feasible.

Nonvitamin K Antagonist Oral Anticoagulant in Patients With Venous Thromboembolism and Polycythemia Vera or Essential Thrombocythemia: A Cohort Study.

ABSTRACT: Thrombosis is the most common adverse event in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Little is known about the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients with myeloproliferative neoplasms. We sought to evaluate the efficacy and safety of NOAC in a cohort of patients with PV and ET, who experienced venous thromboembolism (VTE). We enrolled 48 consecutive patients with PV (70.8%) and ET [median age 67.0 (interquartile range, 58.5-72.0) years], who experienced VTE. Patients received apixaban (39.6%), rivaroxaban (33.3%), or dabigatran (27.1%). During a median follow-up of 30 (interquartile range, 20.5-41.5) months, recurrent thrombotic events and bleeding were recorded. Four thrombotic events (3.3 per 100 patient-years) were reported. Three deep vein thrombosis episodes (2.5 per 100 patient-years) were experienced by 2 patients with PV, who received apixaban (5 mg bid) and dabigatran (150 mg bid), and 1 patient with ET, who received dabigatran (150 mg bid). One ischemic stroke occurred in a patient with PV on rivaroxaban (20 mg/d). There was 1 major bleeding (0.8 per 100 patient-years) in a patient with ET on dabigatran (150 mg bid) and 3 clinically relevant nonmajor bleeding (2.5 per 100 patient-years): 2 on rivaroxaban (20 mg/d) and 1 on apixaban (5 mg bid). We did not observe significant differences related to the type of NOAC. Three deaths (2.5 per 100 patient-years) unrelated to either VTE or bleeding were recorded. This study shows that NOACs may be effective and safe as secondary prevention of VTE in patients with myeloproliferative neoplasms.

Direct Oral Anticoagulants for Venous Thromboembolism Prophylaxis Following Robot-assisted Radical Cystectomy: A Retrospective Feasibility Study at a Single Academic Medical Center.

OBJECTIVES: To evaluate the use of direct oral anticoagulants following radical cystectomy for venous thromboembolism prophylaxis. We compared the experience of those who received venous thromboembolism prophylaxis following a robot-assisted radical cystectomy with either a direct oral anticoagulant or enoxaparin. METHODS: Medical records of 66 patients who underwent robot-assisted radical cystectomy between July 2017 and May 2020 at a single academic institution were reviewed retrospectively. Patients received extended prophylaxis with either a direct oral anticoagulant or enoxaparin before or following surgical discharge. Venous thromboembolic events and complications resulting in emergency department visits and readmissions were reviewed over a 90-day postoperative period. RESULTS: A total of 4 venous thromboembolic events within 90 days of surgery were observed. Among patients taking enoxaparin, 5% (2/37) developed a deep vein thrombosis and 3% (1/37) developed a pulmonary embolism. Among patients taking direct oral anticoagulants, 3% (1/29) developed a deep vein thrombosis. Zero patients in the enoxaparin group and 3% (1/29) of patients in the direct oral anticoagulant group experienced bleeding that required an emergency department visit. CONCLUSION: Direct oral anticoagulants performed comparably to enoxaparin in this feasibility study following robot-assisted radical cystectomy in 66 patients. No significant differences in the number of venous thromboembolisms or bleeding complications were observed. These data encourage future studies and support the prospect of direct oral anticoagulants as a potentially suitable oral alternative to injectable low molecular weight heparins for venous thromboembolism prophylaxis following radical cystectomy.

A multicenter randomized controlled trial comparing administration of antithrombin III after liver resection (HiSCO-05 trial).

BACKGROUND: Posthepatectomy liver failure is a poor prognostic factor after hepatectomy. Various preventive treatments have been tried; however, there are no clinical trials that use posthepatectomy liver failure as the primary endpoint, and the clinical effects of posthepatectomy liver failure have not been fully verified. The aim of this study was to investigate whether administration of antithrombin III can prevent posthepatectomy liver failure in patients with coagulopathy after hepatectomy. This study also evaluated the safety of AT-III administration after hepatectomy. METHODS: The current study enrolled 141 patients diagnosed with coagulopathy after hepatectomy between October 2015 and September 2018 at 7 hospitals in Hiroshima, Japan (HiSCO group). Patients were randomized to undergo either administration of antithrombin III (n = 64) or non-administration (n = 77). The primary endpoint was the incidence of posthepatectomy liver failure. This randomized controlled trial was registered with the University Medical Information Network Clinical Trial Registry (UMIN000018852). RESULTS: Treatment for postoperative coagulopathy was performed safely without adverse events. The incidence of posthepatectomy liver failure was similar in both treatment groups (nonadministration of antithrombin III group, 28.5%, versus administration of antithrombin III group, 28.1%; P = .953) The rate of morbidity was higher in the administration group than the non-administrated group (17.2% vs 11.7%, P = .351). Following the multivariate analysis of the whole study group, body mass index ≥25, total bilirubin ≥1.5 mg/dL, and the disseminated intravascular coagulation score ≥5 postoperatively were the independent risk factors for posthepatectomy liver failure. CONCLUSION: This study showed that the administration of antithrombin III resulted in no significant difference in preventing posthepatectomy liver failure, possibly through suppressing coagulopathy.

Dabigatran Reversal With Idarucizumab in Patients Requiring Urgent Surgery: A Subanalysis of the RE-VERSE AD Study.

OBJECTIVE: To further examine anticoagulation reversal and clinical outcomes in dabigatran treated patients requiring urgent surgery or procedural interventions. BACKGROUND: Idarucizumab, a humanized monoclonal antibody fragment, reverses dabigatran anticoagulation. METHODS: Data from surgical and procedural patients in RE-VERSE AD, a multicenter, open-label, single-arm, prospective cohort of dabigatran reversal were evaluated. A total of 202 patients in this group received 5 g of idarucizumab before surgery or procedures. RESULTS: The interventions included 49 abdominal, 45 orthopedic, 34 vascular, 8 neurologic, and 4 genitourinary surgical procedures, or 29 catheter-based cases, 20 cases for drainage, and 8 diagnostic procedures. Five patients did not undergo their intended intervention after receiving idarucizumab. Complete reversal of the dabigatran anticoagulant effect occurred within minutes in almost all patients, with normal hemostasis in more than 91% of patients. The median time from the first vial of idarucizumab to surgery or procedures was less than 2 hours in all groups except neurosurgery, where it was 3.3 hours. Fresh frozen plasma and packed red cells were the most frequently transfused blood products. Postreversal thromboembolic events occurred in 10 (5%) patients at 30 days, 5 of whom had restarted anticoagulation before the event. Overall 30-day mortality was 12.6%. There were no serious adverse safety signals due to idarucizumab dosing. CONCLUSIONS: Idarucizumab facilitates management of patients requiring urgent procedures by providing rapid dabigatran reversal, and is the only agent of its class studied in surgical patients.

Profile of patients diagnosed with acute venous thromboembolism in routine practice according to age and renal function: RE-COVERY DVT/PE study.

In randomized clinical trials (RCTs) of nonvitamin K antagonist oral anticoagulants (NOACs) for acute venous thromboembolism (VTE), ~ 12-13% of patients were elderly and ~ 26% had mild-to-moderate renal impairment. Observational studies are not restricted by the selection and treatment criteria of RCTs. In this ancillary analysis of the RE-COVERY DVT/PE global observational study, we aimed to describe patient characteristics, comorbidities, and anticoagulant therapy for subgroups of age (< or ≥ 75 years) and renal impairment (creatinine clearance [CrCl; estimated with Cockcroft-Gault formula] < 30 [severe], 30 to < 50 [moderate], 50 to < 80 [mild], ≥ 80 [normal] mL/min). Of 6095 eligible patients, 25.3% were aged ≥ 75 years; 38.2% (1605/4203 with CrCl values) had mild-to-moderate renal impairment. Comorbidities were more common in older patients (73.9% aged ≥ 75 vs. 58.1% < 75 years) and in those with mild or moderate versus no renal impairment (75.9%, 80.9%, and 59.3%, respectively). At hospital discharge or 14 days after diagnosis (whichever was later), most patients (53.7% and 55.1%, respectively) in both age groups received NOACs; 20.8% and 23.4%, respectively, received vitamin K antagonists, 19.0% and 21.8% parenteral therapy, 2.3% and 3.8% other anticoagulant treatments. Use of NOACs decreased with worsening renal impairment (none 58.5%, moderate 49.6%, severe 25.7%) and, in younger versus older patients with moderate renal impairment (33.1% vs. 56.1%). In routine practice, there are more elderly and renally impaired patients with VTE than represented in RCTs. Decreasing renal function, but not older age, was associated with less NOAC use. Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT02596230. Decreasing renal function, particularly in the subgroup with CrCl < 30 mL/min, but not older age, was associated with less use of nonvitamin K antagonist oral anticoagulants (NOACs). Nevertheless, more than half of the older patients with moderate renal impairment received a NOAC as their oral anticoagulant.

Adrenal haemorrhage as a complication of COVID-19 infection.

We report an unusual complication of COVID-19 infection in a 53-year-old Caucasian man. He presented with shortness of breath, fever and pleuritic chest pain. A CT pulmonary angiogram (CTPA) demonstrated acute bilateral pulmonary embolism and bilateral multifocal parenchymal ground glass change consistent with COVID-19 (SARS-CoV-2) infection. Right adrenal haemorrhage was suspected on the CTPA which was confirmed on triple-phase abdominal CT imaging. A short Synacthen test revealed normal adrenal function. He was treated initially with an intravenous heparin infusion, which was changed to apixaban with a planned outpatient review in 3 months' time. He made an uncomplicated recovery and was discharged. Follow-up imaging nearly 5 months later showed near complete resolution of the right adrenal haemorrhage with no CT evidence of an underlying adrenal lesion.

[HCF-ANMCO/AICPR/GIEC/ITAHFA/SICOA/SICP/SIMG/SIT Cardiological Societies Council Consensus document: Anticoagulant therapy in venous thromboembolism and atrial fibrillation of the patient with cancer. Current knowledge and new evidence]. / Documento di consenso della Consulta delle Società Cardiologiche HCF-ANMCO/AICPR/GIEC/ITAHFA/SICOA/SICP/SIMG/SIT: La terapia anticoagulante nel tromboembolismo venoso e nella fibrillazione atriale del paziente con cancro. Le attuali conoscenze e le nuove evidenze.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, either symptomatic or incidental, is a common complication in the history of cancer disease. The risk of VTE is 4-7-fold higher in oncology patients, and it represents the second leading cause of death, after cancer itself. In cancer patients, compared with the general population, VTE therapy is associated with higher rates of recurrent thrombosis and/or major bleeding. The need for treatment of VTE in patients with cancer is a challenge for the clinician because of the multiplicity of types of cancer, the disease stage and the imbricated cancer treatment. Historically, in cancer patients, low molecular weight heparins have been preferred for treatment of VTE. More recently, in large randomized clinical trials, direct oral anticoagulants (DOACs) demonstrated to reduce the risk of VTE. However, in the "real life", uncertainties remain on the use of DOACs, especially for the bleeding risk in patients with gastrointestinal cancers and the potential drug-to-drug interactions with specific anticancer therapies.In cancer patients, atrial fibrillation can arise as a perioperative complication or for the side effect of some chemotherapy agents, as well as a consequence of some associated risk factors, including cancer itself. The current clinical scores for predicting thrombotic events (CHA2DS2-VASc) or for predicting bleeding (HAS-BLED), used to guide antithrombotic therapy in the general population, have not yet been validated in cancer patients. Encouraging data for DOAC prescription in patients with atrial fibrillation and cancer are emerging: recent post-hoc analysis showed safety and efficacy of DOACs for the prevention of embolic events compared to warfarin in cancer patients. Currently, anticoagulant therapy of cancer patients should be individualized with multidisciplinary follow-up and frequent reassessment. This consensus document represents an advanced state of the art on the subject and provides useful notes on clinical practice.

Antithrombin use and mortality in patients with stage IV solid tumor-associated disseminated intravascular coagulation: a nationwide observational study in Japan.

BACKGROUND: Terminal-stage solid tumors are one of the main causes of disseminated intravascular coagulation (DIC); effective therapeutic strategies are therefore warranted. This study aimed to investigate the association between mortality and antithrombin therapy in patients with stage IV solid tumor-associated DIC using a large nationwide inpatient database. METHODS: From July 2010 to March 2018, patients with stage IV solid tumor-associated DIC in the general wards, intensive care unit, or high care unit were identified using the Japanese Diagnosis Procedure Combination Inpatient Database. Patients who received antithrombin within 3 days of admission were allocated to the antithrombin group, while the remaining patients were allocated to the control group. One-to-four propensity score matching analyses were applied to compare outcomes. The primary outcome was the 28-day in-hospital mortality. RESULTS: Of the 25,299 eligible patients, 919 patients had received antithrombin within 3 days of admission and were matched with 3676 patients in the control group. There were no significant differences in the 28-day mortality between the two groups (control vs. antithrombin: 28.9% vs. 30.3%; hazard ratio, 1.08; 95% confidence interval, 0.95-1.23). There were no significant differences in the organ failure score and the proportion of critical bleeding between the two groups. Subgroup analyses showed that the effects of antithrombin were not significantly different among different tumor types. CONCLUSION: Using a nationwide Japanese inpatient database, this study showed that there is no association between antithrombin administration and 28-day mortality in patients with stage IV solid tumor-associated DIC. Therefore, establishing other therapeutic strategies for solid tumor-associated DIC is required.

A Survey of Direct Oral Anticoagulant Cessation in General Surgery and Outcomes in Patients with Nonvalvular Atrial Fibrillation.

There is little data on management and outcomes of atrial fibrillation (AF) patients on direct oral anticoagulants (DOAC) undergoing general surgery.We retrospectively assessed 98 surgeries in 85 nonvalvular AF patients aged 73 ± 8 (59 men) receiving DOACs. Cardiac, emergency, and minimally invasive surgeries were excluded.The CHA2DS2-VASc score ranged from 0 to 8. The DOACs being given were: dabigatran, 16; rivaroxaban, 25; apixaban, 28; and edoxaban, 16. While the DOACs were not suspended in 11 cases, they were interrupted for a median of 2.0 days before surgery and restarted at a median of 3.0 days after surgery. There were 9 complications (9.2%), 3 instances of thromboembolism and 6 bleeding. Thromboembolism occurred at a mean of 3.0 postoperative days, all of which occurred before resumption of DOACs, while bleeding events occurred at a mean of 4.0 postoperative days. Two of the 3 patients with thromboembolism went into cardiopulmonary arrest during the event, but were resuscitated. There were significantly more patients with congestive heart failure or combined antiplatelets in the patients with complications. The complication group had a significantly higher HAS-BLED score and lower preoperative hemoglobin level. There were no significant differences in the management of DOAC interruption between those with complications and without.The perioperative complication rate in nonvalvular AF patients undergoing elective surgery treating with DOACs was 9.2%. Patients with congestive heart failure, receiving combined therapy with antiplatelets, a higher HAS-BLED score, or lower preoperative hemoglobin level were at higher risk. Further studies evaluating the ideal perioperative DOAC protocol are warranted.

Antithrombin Deficiency in Trauma and Surgical Critical Care.

Antithrombin deficiency (ATD) was described in 1965 by Olav Egeberg as the first known inherited form of thrombophilia. Today, it is understood that ATDs can be congenital or acquired, leading to qualitative, quantitative, or mixed abnormalities in antithrombin (AT). All ATDs ultimately hinder AT's ability to serve as an endogenous anticoagulant and antiinflammatory agent. As a result, ATD patients possess higher risk for thromboembolism and can develop recurrent venous and arterial thromboses. Because heparin relies on AT to augment its physiologic function, patients with ATD often exhibit profound heparin resistance. Although rare as a genetic disorder, acquired forms of ATD are seen with surprising frequency in critically ill patients. This review discusses ATD in the context of surgical critical care with specific relevance to trauma, thermal burns, cardiothoracic surgery, and sepsis.

Effects of dabigatran and fondaparinux on degloving injuries: An experimental study.

BACKGROUND: Management of the skin degloving injuries is still a problematic issue, and the avulsed part of the skin may become necrotic. We hypothesized that the anticoagulant pharmacological agents, fondaparinux and dabigatran may be beneficial in the treatment of degloving injuries by enhancing the viability of the reattached flap. METHODS: Twenty four Wistar rats were divided into three groups as follows: control group (Group 1), fondaparinux group (Group 2) and dabigatran group (Group 3). A model of a degloving injury on the tail of rats was developed in all groups. After 15 minutes, the avulsed flaps were sutured back. Group 1 received 1ml/day saline intraperitoneally for 10 days. Group 2 received 0.3 ml/kg/day fondaparinux intraperitoneally for 10 days. Group 3 received 30 mg/kg/day dabigatran orally for 10 days. At the end of the treatments, gross morphological and histopathological tail tissue survivals were evaluated. RESULTS: Histopathological examination of the fondaparinux and dabigatran groups revealed that the tail skin was mostly viable with mild inflammation. The mean necrotic length in tails and severity of inflammation was significantly higher in the control group compared to the fondaparinux and dabigatran groups (p<0.05). No statistically significant differences were noted between the fondaparinux and dabigatran groups in histopathologic evaluations. There was no significant difference in necrosis lengths and the other histopathological parameters between dabigatran and fondaparinux groups. CONCLUSION: Dabigatran and fondaparinux improved tissue survival in skin degloving injuries concerning gross morphological and histopathological findings. However, the findings of this study should be supported and improved by new experimental and especially clinical studies.

Antithrombin gamma attenuates macrophage/microglial activation and brain damage after transient focal cerebral ischemia in mice.

AIMS: Thrombin formation is increased in patients with acute cerebral ischemic stroke, and augments coagulation and inflammation in the brain. Administration of antithrombin (AT) was previously reported to be protective against renal and myocardial ischemic injury. Thus, we hypothesized that treatment with AT would be neuroprotective against cerebral ischemic injury. This study evaluated the effects of AT treatment on ischemic inflammation and brain damage in mice subjected to middle cerebral artery occlusion (MCAO). MAIN METHODS: A mouse model of 4-hour MCAO was used to induce ischemic brain injury. Recombinant AT gamma was administered intravenously immediately after reperfusion at 4 h after MCAO. Infarct volume, neurological deficit, and regional cerebral blood flow (rCBF) were measured at 24 h after MCAO. To evaluate the effect of AT gamma on ischemic inflammation, we measured the number of Iba1-positive cells (marker of macrophage/microglial activation) and levels of proinflammatory cytokines. Further, we investigated the direct anti-inflammatory effects of rAT in the J774.1 cell line. KEY FINDINGS: Treatment with AT gamma (480 U/kg) reduced infarct volume and neurological deficit, and improved rCBF, in MCAO mice. Moreover, AT gamma treatment decreased the number of Iba1-positive cells and levels of proinflammatory cytokines. In vitro, treatment with thrombin significantly increased proinflammatory cytokine levels, which was significantly reduced by pretreatment with AT gamma. SIGNIFICANCE: Treatment with AT showed neuroprotective effects via anticoagulation actions, as well as direct anti-inflammatory effects on macrophage/microglial activation. These data suggest that AT may be a useful new therapeutic option for cerebral ischemia.